The present invention lies in the field of water-soluble antioxidant formulations. More specifically, the present invention lies in the field of hydrolyzable, water-soluble derivatives of probucol compounds for various applications.
Probucol is a potent antioxidant, chemically related to the widely used food additives 2,[3]-tert-butyl-4-hydroxyanisole (BHA) and 2,6-di-tert-butyl-4-methylphenol (BHT). Probucol and various related compounds have been discussed in various patents including the following: U.S. Pat. No. 3,485,843 issued to Wang, U.S. Pat. No. 3,576,833 issued to Neuworth, U.S. Pat. No. 3,862,332 issued to Barnhart et al., and U.S. Pat. No. 4,985,465 issued to Hendler. Its full chemical name is 4,4'-(isopropylidenedithio) bis(2,6-di-tert-butylphenol), and it has the following structure: ##STR1##
Today, probucol is used primarily to lower serum cholesterol levels in hypercholesterolemic patients, but recent work has shown that it also may be used to treat other ailments such as viral and retroviral infections (e.g. human immunodeficiency virus (HIV-1) infection). The anti-viral properties of probucol are discussed in U.S. Pat. No. 4,985,465, which is incorporated herein by reference for all purposes. Probucol has also been claimed to be effective in treating arrhythmia; see U.S. Pat. No. 4,719,237 issued to McCaughan.
Recent evidence suggests that the atherogenic effects of low density lipoprotein (LDL) may be in part mediated through its oxidative modification. Probucol has been shown to possess potent antioxidant properties and to block oxidative modification of LDL. Consistent with these findings, probucol has been shown to actually slow the progression of atherosclerosis in LDL receptor-deficient rabbits as discussed in Carew et al. Proc. Natl. Acad. Sci. U.S.A. 84:7725-7729 (1987) which is incorporated herein by reference for all purposes. Most likely, probucol is effective because it is highly lipid soluble and is transported by lipoproteins, thus protecting them against oxidative damage.
Unfortunately, probucol is almost insoluble in water and therefore cannot be injected intravenously (it is even difficult for cells to take it up in vitro because of its poor miscibility in buffers and media for cell culture). Thus, probucol is commonly administered in the form of tablets available under the trademark Lorelco.TM. (Marion Merrell Dow Pharmaceuticals, Inc., Kansas City, Mo.). However, solid probucol is poorly absorbed into the blood, and is excreted in substantially unchanged form. Further, the tablet form of probucol is absorbed at significantly different rates and in different amounts by different patients. In one study (Heeg et al., Plasma Levels of Probucol in Man After Single and Repeated Oral Doses, La Nouvelle Presse Medicale, 9:2990-2994 (1980)), peak levels of probucol in sera were found to differ by as much as a factor of 20 from patient to patient. In another study, Kazuya et al. J. Lipid Res. 32; 197-204 (1991) observed an incorporation of less than about 1 .mu.g of probucol/10.sup.6 cells when endothelial cells are incubated for 24 h with 50 .mu.M probucol.
The low water-solubility of probucol limits its usefulness in another way. When blood flow to a tissue is interrupted and later re-established, there is a so-called reperfusion injury that is largely due to the development of free radicals and consequent oxidative damage. Every year, thousands of patients having myocardial infarctions are injected with thrombolytic agents in an attempt to reopen thrombosed coronary arteries. These patients are at significant risk of developing reperfusion injury. It has been found that anti-oxidants seem to limit post-perfusion injury. In fact, some studies have shown that probucol given orally for some time before tying off a renal artery in the rat can limit the post-perfusion injury in the kidney. Thus, the simultaneous injection of a potent antioxidant might significantly improve the prognosis of such patients. Unfortunately, it takes days to build up probucol levels by oral administration, and it cannot be predicted when someone will have a myocardial infarction.
The above discussion shows that a need exists for a probucol delivery formulation (preferably an aqueous solution) that is readily absorbed by the patient and can be administered intravenously. Unfortunately, known water-soluble antioxidants do not partition into lipoproteins or other membrane lipids where preoxidation occurs. Thus, the desired formulation should also provide an antioxidant that partitions into lipid containing phases.